The overall goal of this research is to elucidate the role of manganese superoxide dismutase (MnSOD) in the control of cancer development. It has been shown that most tumor cells have reduced MnSOD activity when compared to their normal counterparts. Recent studies have suggested the possibility that MnSOD may function as a new type of cancer suppressor gene. We have demonstrated that the expression of MnSOD suppresses neoplastic transformation and promotes differentiation. It has also been demonstrated in a variety of cancer cell lines that expression of MnSOD reduces tumorigenicity and metastatic capability. However, the specific stage and mechanisms by which MnSOD acts to suppress cancer development are unknown. We hypothesize that MnSOD suppresses tumor development at the promotion stage by modulating the endogenous cellular redox status which regulates the expression and/or activity of oncogenic proteins. To test this hypothesis, an established multistage skin carcinogenesis model will be used. The extent to which MnSOD suppresses cancer development will be determined in control and transgenic mice which express human MnSOD in their skin. The connection between the expression of human MnSOD transgene and 1) the production of mutated genes, 2) the formation of oxidative stress, 3) the expression and activity of proto-oncogenic proteins and their target genes, and 4) the development of inflammation, hyperplasia and skin tumors will be established. We have generated several lines of transgenic mice expressing human MnSOD genes in their skin. The strain of mice in which the transgenic mice were derived has been shown to develop tumors after an application of DMBA and daily applications of TPA. This transgenic mouse model should offer a powerful model for further investigating the tumor suppressor role of MnSOD. The results obtained from this study should provide direct data concerning the role of MnSOD in the process of cancer development and should enhance our understanding of the mechanism by which MnSOD directs the suppression of tumor genesis. This information may lead to the development of novel strategies to modulate the cellular redox status for the control of cancer development and the treatment of fully developed malignancies.